1. Field of the Invention
This invention resides in the field of chiral separations, procedures for performing such separations, and the materials used in the procedures. The separations addressed by this invention are those of chiral drugs, particularly chiral carboxylic acids, in which one enantiomer is superior to the other in therapeutic effect.
2. Description of the Prior Art
Many chiral drugs, particularly homochiral drugs, are known to have enantiomers that perform differently in terms of pharmacological activity, toxicological considerations, or both. One class of chiral drugs that benefit from enantioselectivity are chiral carboxylic acids, notably 2-aryl carboxylic acids. Included among these are flurbiprofen (2-(2-fluoro-4-biphenylyl)-propionic acid), ibuprofen, (2-(4-isobutylphenyl)-propionic acid), naproxen (2-(6′-methoxy-2′-naphthyl)propionic acid), ketoprofen (2-(3-benzoylphenyl)propionic acid), carprofen (6 chloro-α-methyl-9H-carbazole-2-acetic acid), furaprofen (α-methyl-3-phenyl-7-benzofuranacetic acid), cicloprofen (α-methyl-9H-fluorene-2-acetic acid), cliprofen (3-chloro-α-methyl-4-(2-thienylcarbonylbenzene) acetic acid), indoprofen (4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)benzene acetic acid), pirprofen (3-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)benzeneacetic acid), and surprofen (α-methyl-4-(2-thienylcarbonyl)benzeneacetic acid). Disclosures of the benefits of enantioselectivity for these drugs and of methods of achieving their enantioselectivity are found in Zambon Group S.p.A. European Patent Application No. EP 0 719 755 A1, published Jul. 3, 1996, and its counterpart, Pozzoli, C., et al., U.S. Pat. No. 5,840,964, issued Nov. 24, 1998; Hardy, R., et al., International Patent Application Publication No. WO 94/12460, publication date Jun. 9, 1994, and its counterpart, Hardy, R., et al., U.S. Pat. No. 5,599,969, issued Feb. 4, 1997; Sunshine, A., et al., U.S. Pat. No. 5,286,751, issued Feb. 15, 1994; and Iredale, J., et al., “The Effects of pH and Alcoholic Organic Modifiers on the Direct Separation of Some Acidic, Basic and Neutral Compounds on a Commercially Available Ovomucoid Column,” Chromatographia 31 (7/8), 329-334 (1991).
For any chiral drug of which one enantiomer is therapeutically superior to the other, administration of the desired enantiomer in isolated form will give the drug its maximal effect, and a number of analytical and preparative procedures have been developed for this purpose. These include manufacturing procedures, such as asymmetric synthesis and biocatalysis, that produce the desired enantiomer directly. The alternative to enantioselective manufacturing is the isolation or purification of the desired enantiomer from a racemic mixture. Purification techniques that have been developed for this purpose include crystallization, chemical resolution, the use of chiral membranes, and chiral chromatography. Chiral chromatography has the potential of being the most efficient since it does not involve the specialized synthesis steps involved in asymmetric synthesis or the additional processing steps involved in chemical resolution such as salt formation and product recovery from the salt. Nor is chiral chromatography plagued by the low yields that are typical of both crystallization techniques and techniques involving chiral membranes. The appeal of chiral chromatography has led to the development of a variety of chiral chromatographic techniques based on liquid, gas, subcritical fluid, and supercritical fluid chromatography, and a variety of chiral stationary phases.
One means of achieving peak separation in chiral chromatography is the use of a solvent mixture containing a non-polar solvent such as hexane or heptane and one or more alcoholic compounds. The retention of enantiomers is dependent on the polarity of the mobile phase and hence the separation can be tuned by variation of the ratio of alcohol to non-polar solvent. This use of alcohols is disclosed in Iqbal, R., et al., “Chiral separations in microemulsion electrokinetic chromatography—Use of micelle polymers and microemulsion polymers,” J. Chromatog. A 1043 (2004) 291-302. This paper reports the use of 1-butanol and n-heptane in combination with a microemulsion of polysodium N-undecenoyl-D-valinate in a capillary electrophoresis column. Another disclosure of the use of alcohols is Wang, T., et al., “Effects of alcohol mobile-phase modifiers on the structure and chiral selectivity of amylase tris(3,5-dimethylphenylcarbamate) chiral stationary phase,” J. Chromatog. A 1015 (2003) 99-110. In this paper, Wang et al. report the use of isopropanol, t-butyl alcohol, and ethanol in high-performance liquid chromatography (HPLC). Still another disclosure is found in Iredale, J., et al. (1991), cited above, which reports the use of various C1-C4 alcohols as mobile phase modifiers in an HPLC column in which the stationary phase is an ovomucoid protein on a silica support.
In traditional chromatography, the problems of peak separation are often addressed by increasing the path length of the solutes through the separation medium. This can be impractical, however, since it may require excessive column lengths and the high back pressures that typically occur with long columns. One class of chromatographic methods that improves performance for difficult separations is Multi-Column Continuous Chromatography (MCC), of which one mode of operation is Simulated Moving Bed (SMB) chromatography. SMB has achieved wide recognition for chiral separations. In SMB, the mobile phase flows in counter-current manner against the “stationary” phase (solid media), allowing the mixture to be separated to flow in a continuous flow, thereby potentially increasing the throughput of the process. To achieve this in practical application, a series of packed-bed columns are arranged in series in a ring formation that is divided into sections, typically four such sections for SMB, with one or more columns per section. Only the mobile phase and the points of inlet and outlet around the ring are moved while the beds themselves remain stationary. Two fluid inlets (one for feed and the other for eluent) and two fluid outlets (one for extract and the other for raffinate) are distributed around the ring of columns such that the inlets alternate with the outlets. The mobile phase moves in one direction around the ring, while at regular intervals of time the inlets and outlets are switched, traveling around the circle in the same direction as the mobile phase flow. Each port thus alternates between serving as an inlet and as an outlet, and between the two types of inlet as well as the two types of outlet. Descriptions of SMB chromatography and its use in separating enantiomers are found in Miller, L., et al., “Chromatographic resolution of the enantiomers of a pharmaceutical intermediate from the milligram to the kilogram scale,” J. Chromatog. A, 849, no. 2, 309-317 (1999); Negawa, M., et al., U.S. Pat. No. 5,434,298 (issued Jul. 18, 1995); Nagamatsu, S., et al., U.S. Pat. No. 6,217,774 (issued Apr. 17, 2004); Ikeda, H., et al., U.S. Pat. No. 6,533,936 (issued Mar. 18, 2003); Ohnishi, A., et al., United States Patent Application Publication No. US 2005/0054878 A1, published Mar. 10, 2005; and Chiral Separation Techniques—A Practical Approach, 3d ed., Subramanian, G., ed., Wiley-VCH Verlag GmbH & Co. KGaA, Wernheim, Germany (2007).
When separating acidic or basic racemates, the inclusion of an organic acid or organic base modifier in the mobile phase is recommended to improve the separation by achieving a better peak shape. Carboxylic acids such as acetic acid, trifluoroacetic acid, and formic acid have been used for this purpose in separations of chiral carboxylic acids. A disclosure of the use of this type of modifier is found in Chiral Separation Techniques—A Practical Approach, 3d ed., Subramanian, G., ed., Wiley-VCH Verlag GmbH & Co. KGaA, Wernheim, Germany (2007). The combination of an acidic modifier with an alcohol thus produces a system that will provide optimal conditions for the separation. Unfortunately, at production-scale separations where the system components remain in contact for extended periods of time, the alcohols and the acid will combine to form an ester, reducing the yield and the final purity of the product.